Diabetes mellitus is a clinical syndrome caused by the interaction of various factors including genetic traits and environmental contributors. Diabetes is primarily divided into type I and type II. Wherein, the basic pathophysiologic mechanism of type I diabetes mellitus relates to absolute hyposecretion of insulin, which is treated clinically mainly by supplementing insulin and thus is also named as insulin dependent diabetes mellitus. Over 95% of the patients are suffering from type II diabetes mellitus. In the clinical research, it is found that most of the patients suffering from type II diabetes mellitus can synthesize normal or even excessive insulin, but since the sensitivity of target cell to insulin is decreased (which is also named as “insulin resistance”), which causes the relative insufficiency of insulin, it is also named as non-insulin dependent diabetes mellitus. Insulin resistance is a key factor during the occurrence and development of type II diabetes mellitus.
Since the pathogenesis for the above two types of diabetes mellitus are different, the drugs for treating them are far different. At present, the drugs for treating type I diabetes mellitus mainly include exogenous insulin (including genetically recombinant human insulin and animal insulin), drugs having insulin-like effect, insulin-like growth factor-1 and Jin Qi hypoglycemic tablet, etc. The drugs for treating type II diabetes mellitus include sulphonylureas, biguanides, other insulin sensitizers and auxiliary means, etc.
After the sulphonylurea hypoglycemic drugs bind to the receptors of pancreatic islet β-cell membrane, the potassium ion channels are closed, thereby blocking flowout of potassium ion and inducing depolarization of the cell membrane, so that the Ca2+ channels are opened to allow the extracellular calcium ions to flow inward. The increase in the concentration of intracellular calcium ions triggers the release of insulin. Sulphonylurea hypoglycemic drugs can be divided into two generations according to their time of coming into existence. The first generation includes tolpropamide, and the second generation includes glibenclamide (diabeta), gliclazide (diamicron), glipizide (minidiab) and gliquidone, etc.
Biguanide hypoglycemic drugs can inhibit appetite, improve the binding of insulin to the receptors, promote the anaerobic glycolysis of glucose in cells, inhibit tissue respiration and inhibit hepatic gluconeogenesis. The biguanide hypoglycemic drugs mainly include metformin, phenformin and buformin.
Other hypoglycemic drugs mainly include thiazolidinedione drugs (such as troglitazone, rosiglitazone, and pioglitazone, etc.), β3-adrenoceptor regulators, glucagon receptor antagonists, fatty acid metabolism interfering agents, α-glycosidase inhibitors (such as acarbose, voglibose, miglitol, etc.), and aldose reductase inhibitors and the like.
The deep research on glycometabolism-related endogenous peptide hormone provides a new idea for the treatment of diabetes mellitus. When human body intakes nutrient materials, the enteroendocrine cells release enteropeptide hormone, mainly including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which regulates the metabolism of organism by affecting the insulin generation, gastrointestinal peristalsis, pancreatic islet cell proliferation, etc. Wherein, GLP-1 is secreted by the enteric Langerhans cells, and activates adenylate cyclase to improve the cAMP level by specifically binding to the GLP-1 receptor of pancreatic islet β-cells, so as to further activate the protein kinase. The metabolic signal (glycometabolism) and kinase signal (binding to GLP-1) cooperate at the cell membrane level to finally cause the Ca2+ channel to open and Ca2+ to flow inward, thereby further stimulating the secretion of insulin while inhibiting the generation of glucagon, so that the postprandial blood sugar concentration is decreased and maintained at a constant level. Also, GLP-1 has the function of neuroregulation, and can retard gastric emptying and inhibit appetite. Normally, the effect of GLP-1 for stimulating insulin secretion depends on the blood sugar concentration. As the blood glucose concentration lowers, the effect of GLP-1 for stimulating insulin secretion accordingly decreases, namely self-limited hypoglycemic effect, and thus hypoglycemia will not occur. The drugs with the GLP-1-like action are greatly desirable for the treatment of diabetes mellitus.
GLP-1, which is directly injected to the patients with diabetes for continued 6 weeks, may effectively control the levels of blood sugar and free fatty acids, and improve the function of β-cells. Since the half life of GLP-1 in body is less than 5 minutes, its clinical application is greatly limited. A GLP-1 analog that binds to albumin, as developed by Novo Nordisk Co., Danmark (Trade Name “Liraglutide”), may have a half life of up to 10 hours. The result of Clinical Trial Phase I showed that the drug can obviously improve the symptoms of diabetes mellitus while having no notable virulent side-effect. It can be predicted that Clinical Trial Phase III will be carried out before long. Exendin-4 (also named as AC2993, with the trade name of Exenatide) is a GLP-1 analog (a polypeptide composed of 39 amino acids) developed by the Amylin Medical Co., USA, which was originally isolated from the saliva of an American venomous lizard. In the clinical trials, it is found that, for normal volunteers, Exendin-4 can retard gastric emptying, inhibit appetite and stimulate insulin secretion; for the patients with diabetes of type II, Exendin-4 may stimulate insulin secretion, and obviously decrease the postprandial concentrations of blood sugar and glucagon, and can reduce the body weight of the patients after a long-time use. The side effects resulted therefrom mainly include temporary headache, nausea and vomit. Exendin-4 had been authorized by the American FDA to be marketed as the drugs for treating diabetes of type II at the end of April in 2005. Owing to the use of the Medisorb controlled release technology of Alkerme Co., the controlled release preparation based on Exendin-4, AC2993LAR, as developed by Amylin Co., only needs to be injected once a month, which is being in the Clinical Trial Phase II. Basing on the effect of GLP-1R agonists for promoting the growth and proliferation of pancreatic islet β-cell, American NIH has started the Clinical Trial Phase I of using Exendin-4 (AC2993) to treat type I diabetes mellitus. Since the polypeptide drugs are inconvenient for oral administration, the various international pharmaceutical organizations focus on searching for non-peptide GLP-1R regulators and developing new types of drugs treating diabetes mellitus that have independent intellectual property. However, there are no reports about non-peptide GLP-1R regulators now, except for GLP-1 and analogs thereof.